title: Dihydroxylphenyl amides as inhibitors of the Hsp90 molecular chaperone.
abstract: Information from X-ray crystal structures were used to optimize the potency of a HTS hit in a Hsp90 competitive binding assay. A class of novel and potent small molecule Hsp90 inhibitors were thereby identified. Enantio-pure compounds 31 and 33 were potent in PGA-based competitive binding assay and inhibited proliferation of various human cancer cell lines in vitro, with IC(50) values averaging 20 nM.
authors.affiliation: Pfizer Global Research and Development, La Jolla Laboratories, 10770, Science Center Dr., San Diego, CA 92121, USA. peipei.kung@pfizer.com
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Kung
authors.forename: Lee
authors.initials: L
authors.lastname: Funk
authors.forename: Jerry
authors.initials: J
authors.lastname: Meng
authors.forename: Michael
authors.initials: M
authors.lastname: Collins
authors.forename: Joe Zhongxiang
authors.initials: JZ
authors.lastname: Zhou
authors.forename: M Catherine
authors.initials: MC
authors.lastname: Johnson
authors.forename: Anne
authors.initials: A
authors.lastname: Ekker
authors.forename: Jeff
authors.initials: J
authors.lastname: Wang
authors.forename: Pramod
authors.initials: P
authors.lastname: Mehta
authors.forename: Min-Jean
authors.initials: MJ
authors.lastname: Yin
authors.forename: Caroline
authors.initials: C
authors.lastname: Rodgers
authors.forename: Jay F
authors.initials: JF
authors.lastname: Davies
authors.forename: Eileen
authors.initials: E
authors.lastname: Bayman
authors.forename: Tod
authors.initials: T
authors.lastname: Smeal
authors.forename: Karen A
authors.initials: KA
authors.lastname: Maegley
authors.forename: Michael R
authors.initials: MR
authors.lastname: Gehring
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000596:Amino Acids / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism; D008968:Molecular Conformation; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000596:Amino Acids; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones